Prostate, breast, colorectal and urothelial cancers are common cancer forms. Once the cancer has spread, the prognosis is poor. The treatment for all these forms of cancer is radical surgery, hormone therapy, radiations and cytostatic treatment or combination of these.
Avermectins or avermectin compounds represent a group of macrocyclic lactones originally isolated from the fermentation broth of the strain Streptomyces avermitilis. Such compounds are currently used as antiparasitic agents and mainly as veterinary medicines. However, the avermectin substance ivermectin (22,23-dihydroavermectin B1a+22,23-dihydroavermectin B1b) is a known drug also for humans against certain tropical infections with minor or no side effects. It is the therapy of choice based on oral or parenteral administration against a range of nematodes and parasites (Hotson I K. The avermectins: A new family of antiparasitic agents. J S Afr Vet Assoc 1982; 53(2):87-90). The substance ivermectin has previously been described to induce cell death at low micromolar concentrations in acute myeloid leukemia cell lines. However, the exact mechanism of ivermectin remains to be demonstrated.
Sharmeen et al. (The anti-parasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells, Blood 2010; 116(18): 3593-603) demonstrated a reduction in tumor growth in three independent mouse models of leukemia using concentrations that is pharmacological achievable. Surprisingly the effect on two prostate cancer cell lines was not so pronounced.
Similar to this, Drinyaev et al. (Antitumor effect of avermectins, EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER SCIENCE, NL, vol. 501, no, 1-3, 6 Oct. 2004, p. 19-23), describe an anti-tumor effect on different carcinomatosis models performed in mice. However, no effect was seen without the presence of vincristine, a known and well described alkaloid used for chemotherapy.
Ketoconazole, ibuprofen, diclofenac and celecoxib have been used in experimental studies with tumor cells. Ketoconazole has previously been described to reduce growth of colon adenocarcinoma cells (Kota B P, Allen J D, Roufogalis B D. The effect of vitamin D3 and ketoconazole combination on VDR-mediated P-gp expression and function in human colon adenocarcinoma cells: implications in drug disposition and resistance. Basic Clin Pharmacol Toxicol; 109(2):97-102) and the effect in reduction of tumor growth in the prostate has also been explored (Figg W D, Woo S, Zhu W, Chen X, Ajiboye A S, Steinberg S M, et al. A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer. J Urol; 183(6):2219-26.).
Ibuprofen (NSAID) has been described to reduce tumor spread in colorectal cancer (Ruder E H, Laiyemo A O, Graubard B I, Hollenbeck A R, Schatzkin A, Cross A J. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol; 106(7): 1340-50).
Diclofenac (NSAID) has been described to decrease the effect on tumor growth in an experimental model in mice with colorectal metastasis.
Celecoxib has previously been described to enhance radiation therapy in human lung cancer and in different tumor cell lines (Kim Y M, Pyo H. Cooperative Enhancement of Radiosensitivity After Combined Treatment of 17-(Allylamino)-17-Demethoxygeldanamycin and celecoxib in Human Lung and Colon Cancer Cell Lines. DNA Cell Biol).
Until today many of the treatment possibilities for patients suffering from cancer diseases result in advanced surgery, or long time treatment with chemotherapy or radiation. The present study demonstrates that the avermectin compounds, alone or in combination with an imidazole antifungal compound and/or a non-steroidal anti-inflammatory drug (NSAID) in micromolar concentrations reduces the cell proliferation rate in five different human tumor cell lines, from four different locations. All cell lines exhibit reduced proliferation rate at 100 micromolar and several of said combinations at even lower concentrations. Using the composition of the invention in the treatment of different human tumor diseases opens up new strategies in cancer treatment.